Upper Urinary Tract Urothelial Cell Carcinoma

3. EPIDEMIOLOGY AETIOLOGY AND PATHOLOGY

3.1. Epidemiology

Urothelial carcinoma (UC) is the second most common urological malignancy in developed countries [7]. They can be localised in the lower (bladder and urethra) and/or the upper (pyelocaliceal cavities and ureter) urinary tract. Bladder cancer (BC) accounts for 90–95% of UCs whilst upper tract urothelial carcinomas (UTUC) account for only 5–10% of UCs with an estimated annual incidence in Western countries of almost two cases per 100,000 inhabitants [1]. This rate has risen in the past few decades likely as a result of improved detection and the aging population [8,9].

The peak incidence is in individuals aged 70–90 years and UTUC is twice as common in men [10]. A retrospective international registry including data from 2,380 patients diagnosed between 2014 and 2019 (101 centres from 29 countries) confirmed that UTUC patients were predominantly male (70.5%) and 53.3% were past or present smokers. The majority of patients (53%) were diagnosed after they presented with symptoms, mainly visible haematuria [11]. This was confirmed by a meta-analysis pooling 44 studies that showed a pooled UTUC incidence rate of 0.75% in patients with visible haematuria and 0.17% for those with non-visible haematuria [12]. In addition, approximately two-thirds of patients who present with UTUCs have muscle-invasive disease at diagnosis compared to 15–25% of patients diagnosed with de novo BC [13]. The higher incidence of muscle-invasive disease in UTUC vs. BC has been confirmed in population-based studies from Germany and England suggesting that muscle-invasive UTUC represents approximately half of incident cases in recent years [14,15]. Approximately 9% of patients present with metastasis [8,16-18].

Pyelocaliceal tumours are approximately twice as common as ureteral tumours and multifocal tumours are found in approximately 10–20% of cases [19]. The presence of concomitant carcinoma in situ of the upper tract is between 11% and 36% [8]. In 17% of cases, concurrent BC is present [20] whilst a prior history of BC is found in 41% of American men but in only 4% of Chinese men [21]. This, along with genetic and epigenetic factors, may explain why Asian patients present with more advanced and higher-grade disease compared to other ethnic groups [8].

Following treatment, recurrence in the bladder occurs in 29% of UTUC patients, depending on patient-, tumour- and treatment-specific characteristics [22] compared to a 2–5% recurrence rate in the contralateral upper tract [23]. 

Upper tract UC and BC exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumours, BC and UTUC are often clonally related. Genomic characterisation of UTUC provides information regarding the risk of bladder recurrence and can identify tumours associated with Lynch syndrome [24].

Regarding UTUC occurring in patients with BC, of 82 patients treated with intravesical bacillus Calmette-Guérin (BCG) for high-risk BC who had regular upper tract imaging between years 1 and 3, 13% developed UTUC, all of which were asymptomatic [25], whilst in another series of 307 patients without routine upper tract imaging the incidence of UTUC after BC was 25% [26]. A multicentre cohort study (n = 402) with a 50 month follow-up demonstrated a UTUC incidence of 7.5% in NMIBC patients receiving BCG with predictors being intravesical recurrence and non-papillary tumour at transurethral resection of the bladder (TURB) [27]. Following radical cystectomy for MIBC, 3–5% of patients develop a metachronous UTUC [28,29].

3.2. Risk factors

3.2.1. Environmental risk factors

A number of environmental risk factors have been implicated in the development of UTUC [19,30]. Published evidence in support of a causative role for these factors is not strong, with the exception of smoking and aristolochic acid. Tobacco exposure increases the relative risk of developing UTUC by 2.5 to 7.0 fold [31-33]. A large population-based study assessing familial clustering in relatives of UC patients, including 229,251 relatives of case subjects and 1,197,552 relatives of matched control subjects, has demonstrated genetic or environmental roots independent of smoking-related behaviours. With more than 9% of the cohort being UTUC patients, clustering was not seen for UTUC. This suggests that the familial clustering of UC is specific to the lower urinary tract (i.e., BC) [34].

Aristolochic acid, a nitrophenanthrene carboxylic acid produced by aristolochia plants, which are used worldwide for different health-related issues, especially in China and Taiwan [35], exerts negative effects on the urinary system. Aristolochic acid irreversibly injures renal proximal tubules resulting in chronic tubulointerstitial disease, while the mutagenic properties of this carcinogen can lead to UTUC [35-37]. Aristolochic acid has been linked to BC, renal cell carcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma [38]. Two routes of exposure to aristolochic acid are known: (i) environmental contamination of agricultural products by aristolochia plants, as reported for Balkan endemic nephropathy [39]; and (ii) ingestion of aristolochia-based herbal remedies [40,41]. Following bioactivation, aristolochic acid reacts with genomic DNA to form aristolactam-deoxyadenosine adducts [42]; these lesions persist for decades in target tissues, serving as robust biomarkers of exposure [43]. These adducts generate a unique mutational spectrum, characterised by A>T transversions located predominately on the non-transcribed strand of DNA [38,44]. However, it is estimated that less than 10% of individuals exposed to aristolochic acid develop UTUC [37].

Two retrospective series demonstrated that aristolochic acid-associated UTUC is more common in females [45,46]. However, females with aristolochic acid UTUC have a better prognosis than their male counterparts. Consumption of arsenic in drinking water and aristolochia-based herbal remedies together appears to have an additive carcinogenic effect [47]. In Taiwan and Chile, the presence of arsenic in drinking water has been tentatively linked to UTUC [48,49].

In addition, alcohol consumption may be associated with development of UTUC. A large case-control study (1,569 cases and 506,797 controls) has evidenced a significantly higher risk of UTUC in ever-drinkers compared to never-drinkers (OR: 1.23; 95% CI: 1.08–1.40, p = 0.001). Compared to never-drinkers, the risk threshold for UTUC was > 15 g of alcohol/day. A dose-response has been observed [50].

3.2.2. Genetic risk factors

Lynch syndrome is characterised by a predisposition to early onset colorectal cancer and several extra-colonic malignancies related to pathogenic germline mutations in one allele of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. After colorectal and endometrial cancers, UTUC is the 3rd most common malignancy in the Lynch syndrome spectrum [51]. Identifying Lynch Syndrome’s related UTUCs has important clinical implications for both the patient and their relatives given the high risk of developing subsequent multiple different malignancies in the carrier and the strong hereditary predisposition of this condition. Germline mutations in MMR genes are found in 9% of patients with UTUC compared to 1% of patients with BC [52].

From a genetic perspective, the majority of tumours develop in MSH2 and MSH6 mutation carriers [53]. The carcinogenesis is related to the somatic mutation of the second allele of the germline-mutated MMR gene. This will result in a deficient MMR (dMMR) system related to the loss of the expression of the corresponding protein MLH1, MSH2, MSH6 or PMS2 in immunochemistry, which can be responsible for a microsatellite instability identified using the PCR method.

From a clinical perspective, although the PREMM5 model has been developed to estimate the cumulative probability of an individual to carry a germline mutation related to the Lynch syndrome [54], the Amsterdam II criteria remains predominantly used to identify families that are at increased risk of Lynch syndrome [55]. The latter include:

1. At least three relatives with a Lynch-associated cancer (colorectal, endometrium, small bowel or UTUC);
2. A first degree relative to the other two;
3. At least two successive affected generations;
4. At least one relative diagnosed before the age 50;
5. Exclusion of familial adenomatous polyposis in the colorectal cancer cases;
6. Pathological confirmation of the diagnosis.

A study of 115 consecutive UTUC patients reported that 13.9% screened positive for potential Lynch syndrome using the Amsterdam II criteria and 5.2% had confirmed Lynch syndrome [56].

Another UTUC-specific study has suggested that an age <60 at initial diagnosis and a personal history of any other Lynch-related malignancy could be both associated with an increased risk of Lynch syndrome in these patients [57]. A simplified screening tool for UTUC patients has been proposed including these two criteria associated with two others deriving from the Amsterdam II criteria and including one-first degree relative with Lynch-related cancer diagnosed before 50 and two first-degree relatives with Lynch-related cancer regardless of age [58]. Using this simplified screening tool, the proportion of UTUC patients with a suspicion of Lynch-related disease could be more than 20% [58]. Importantly, patients with UTUC who are identified at high risk for Lynch syndrome based on clinical criteria should undergo germline DNA sequencing and family counselling [59,60] (Figure 3.1). Nonetheless, given the limited diagnostic performance of clinical criteria, UTUC patients without suspicion for genetic predisposing factors could be tested for MSI or dMMR using PCR or immunochemistry, respectively. As for any clinical suspicion of hereditary UTUC, those with positive test should also undergo germline DNA sequencing and family counselling [52,61-64] (Figure 3.1).

Figure 3.1: Selection of patients with UTUC for Lynch syndrome screening during the first medical interview*These patients may benefit from MMR deficiency screening using PCR or IHC. Positive result should prompt subsequent testing for germline DNA sequencing mutations.
MMR = mismatch repair; mismatch repair genes = MLH1, MSH2, MSH6, and PSM2; UTUC = upper urinary tract urothelial carcinoma.

Other germline mutations in MSH2, BRCA2, BRCA1 and BRIP1 has been shown to significantly increase the risk of developing UTUC in Chinese patients [65]. Differences in the exposure and susceptibility to carcinogens such as smoking may explain the differences in susceptibility to genetic predisposing mutations to overt disease. Some genetic polymorphisms are associated with an increased risk of cancer or faster disease progression that introduces variability in the inter-individual susceptibility to the risk factors previously mentioned. Upper urinary tract UCs may also share some risk factors and described molecular pathways with bladder UC [24]. So far, two UTUC-specific polymorphisms have been reported [66].

3.2.3. History of bladder cancer

A history of BC is associated with a higher risk of developing UTUCs (see Section 3.1). Patients requiring ureteral stenting at the time of TURB, including prior to radical cystectomy, have been shown to have a higher risk for upper tract recurrence [67,68].

3.3. Histology and classification

3.3.1. Histological types

Upper urinary tract tumours are almost always UCs with pure non-urothelial histology being rare [69,70]. However, histological subtypes are present in approximately 25% of UTUCs [71,72]. Pure squamous cell carcinoma of the urinary tract is often assumed to be associated with chronic inflammatory diseases and infections arising from urolithiasis [73,74]. Urothelial carcinoma with divergent squamous differentiation (i.e., squamous subtype) is present in approximately 15% of cases [73]. Keratinising squamous metaplasia of urothelium is a risk factor for squamous cell cancers and therefore mandates surveillance. Upper urinary tract UCs with different subtypes are high- grade and have a worse prognosis compared to pure UC [72,75,76]. Other subtypes, although rare, include sarcomatoid with inverted growth also being is frequent in the UUT [76,77].

Collecting duct carcinomas, which may seem to share similar characteristics with UCs, display a unique transcriptomic signature similar to renal cancer, with a putative cell of origin in the distal convoluted tubules. Therefore, collecting duct carcinomas are considered as renal tumours [78].

3.4. Molecular background of UTUCs

A number of studies focusing on molecular classification have been able to demonstrate genetically distinct groups of UTUC by evaluating DNA, RNA and protein expression. The most common genomic alterations included FGFR3, chromatin remodelling genes (i.e., KMT2D and KDM6A), TP53/MDM2, and other typical tumour suppressors/oncogenes such as CDKN2A or RAS [79]. Low-grade tumours are enriched for activating FGFR3 mutations (> 90% tumours) and depleted of TP53/MDM2 mutations, whereas high-grade tumours often show mutations in TP53 signalling [80]. It has also been shown that UTUC has a T-cell depleted immune contexture and activated FGFR3 signalling [81]. Five different molecular subtypes with different gene expression, tumour location and outcome have been identified, but, as yet, it is unclear whether these subtypes will respond differently to treatment and therefore, these subtypes have limited use in daily practice [82].

3.5. Summary of evidence and recommendations for epidemiology, aetiology, and histology